Efficacy, Safety, and Immunology of an Inactivated Alum-Adjuvant
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Articles E ffi cacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial Feng-Cai Zhu, Fan-Yue Meng, Jing-Xin Li, Xiu-Ling Li, Qun-Ying Mao, Hong Tao, Yun-Tao Zhang, Xin Yao, Kai Chu, Qing-Hua Chen, Yue-Mei Hu, Xing Wu, Pei Liu, Lin-Yang Zhu, Fan Gao, Hui Jin, Yi-Juan Chen, Yu-Ying Don g, Yong-Chun Liang, Nian-Min Shi, Heng-Ming Ge, Lin Liu, Sheng-Gen Chen, Xing Ai, Zhen-Yu Zhang, Yu-Guo Ji, Feng-Ji Luo, Xiao-Qin Chen, Ya Zhang, Li-Wen Zhu, Zheng-Lun Liang, Xin-Liang Shen Summary Lancet 2013; 381: 2024–32 Background A vaccine for enterovirus 71 (EV71) is needed to address the high burden of disease associated with Published Online infection. We assessed the effi cacy, safety, immunogenicity, antibody persistence, and immunological correlates of an May 29, 2013 inactivated alum-adjuvant EV71 vaccine. http://dx.doi.org/10.1016/ S0140-6736(13)61049-1 Methods We did a randomised, double-blind, placebo-controlled, phase 3 trial. Healthy children aged 6–35 months See Comment page 1968 from four centres in China were randomly assigned (1:1) to receive vaccine or alum-adjuvant placebo at day 0 and 28, Jiangsu Provincial Center for Disease Control and Prevention, according to a randomisation list (block size 30) generated by an independent statistician. Investigators and Nanjing, Jiangsu, China participants and their guardians were masked to the assignment. Primary endpoints were EV71-associated hand, (F-C Zhu MSc, F-Y Meng MSc, foot, and mouth disease (HFMD) and EV71-associated disease during the surveillance period from day 56 to month 14, J-X Li MSc, H Tao BS, K Chu MSc, analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01508247. Y-M Hu BS); Department of Clinical Microbiology and Immunology, College of Findings 10 245 participants were enrolled and assigned: 5120 to vaccine versus 5125 to placebo. 4907 (with three cases Pharmacy, Third Military of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4939 (with 30 cases of EV71-associated Medical University & National HFMD and 41 cases of EV71-associated disease) were included in the primary effi cacy analysis. Vaccine effi cacy was Engineering Research Center for Immunological Products, 90·0% (95% CI 67·1–96·9) against EV71-associated HFMD (p=0·0001) and 80·4% (95% CI 58·2–90·8) against Chongqing, China (F-C Zhu, EV71-associated disease (p<0·0001). Serious adverse events were reported by 62 of 5117 (1·2%) participants in the J-X Li); Beijing Vigoo Biological, vaccine group versus 75 of 5123 (1·5%) in the placebo group (p=0·27). Adverse events occurred in 3644 (71·2%) Beijing, China (X-L Li MSc, versus 3603 (70·3%; p=0·33). Y-T Zhang PhD, Q-H Chen MSc, X-L Shen MSc); National Institute for Food and Drug Interpretation EV71 vaccine provides high effi cacy, satisfactory safety, and sustained immunogenicity. Control, Beijing, China (Q-Y Mao PhD, X Yao PhD, Funding China’s 12–5 National Major Infectious Disease Program, Beijing Vigoo Biological. X Wu MSc, F Gao MSc, Z-L Liang PhD); School of Public Health, Southeast University, Introduction the effi cacy and safety of the vaccine for prevention of Nanjing, Jiangsu, China Disease associated with enterovirus 71 (EV71) infection disease associated with EV71. (P Liu PhD, H Jin PhD, was fi rst described by Schmidt and colleagues in 1974,1 Y-J Chen MSc, Y-Y Dong MSc); Lianyungang City Center for who reported 20 patients with CNS disease—including Methods Disease Control and Prevention, one who died—in California, USA, between 1969, Study design and participants Lianyungang, Jiangsu, China and 1972. Since then, outbreaks of hand, foot, and We did this randomised, double-blind, placebo-controlled (L-Y Zhu BS); Baoying County mouth disease (HFMD) associated with EV71 infec- phase 3 trial in children aged 6–35 months at four centres Center for Disease Control and 2–5 Prevention, Yangzhou, Jiangsu, tion have been reported world wide —particularly in in China ( Donghai, Pizhou, and Baoying counties in China (Y-C Liang BS, S-G Chen BS, infants and young children—accounting for more than Jiangsu province, and Chaoyang district in Beijing) Y-G Ji BS, L-W Zhu BS); Chaoyang 6 000 000 cases and more than 2000 deaths in the past covering 32 townships and 485 villages from January, District Center for Disease decade.6 EV71 infection is associated with various 2012, to March, 2013. Eligibility was assessed by medical Control and Prevention, Beijing, China (N-M Shi MSc, X Ai MSc, diseases including HFMD, herpangina, neurological history inquiry and physical examination. Exclusion F-J Luo MSc); Donghai County signs (aseptic meningitis or encephalitis) with or without criteria included: history of HFMD, previous vaccination Center for Disease Control and serious sequelae, and nonspecifi c illnesses—eg, febrile with EV71 vaccine, acute febrile disease at recruitment, Prevention, Lianyungang, illness, viral exanthem, respiratory infection.6–8 A vaccine and taking any immunosuppressive drugs, blood Jiangsu, China (H-M Ge BS, Z-Y Zhang BS, X-Q Chen BS); and for EV71 is urgently needed to prevent and control products, drugs under investigation, inactivated vaccines, Pizhou County Center for epidemics of EV71.9,10 or attenuated live vaccines within a defi ned period Disease Control and Prevention, Phase 1 and phase 2 trials have assessed the safety (appendix p 3 shows full criteria). The proportion of Xuzhou, Jiangsu, China (L Liu BS, Y Zhang BS) and immunogenicity of an inactivated alum-adjuvant enrolled children in every township was less than 40% of EV71 vaccine in adults, children, and infants.5,11,12 We did the total number of children aged 6–35 months, to avoid this phase 3 trial in young children and infants to assess creating herd immunity in study areas (appendix p 4). 2024 www.thelancet.com Vol 381 June 8, 2013 Articles The study was approved by the institutional review epidemiological, and laboratory data to confi rm EV71- Correspondence to: board of Jiangsu Provincial Center of Disease Control associated disease, and serious adverse events attributed Feng-Cai Zhu, Jiangsu Provincial and Prevention, and done in accordance with the to vaccine. The committee was not involved in any other Center for Disease Control and Prevention, Jiangsu Road, Declaration of Helsinki, Good Clinical Practice, and part of the study. Nanjing 210009, Jiangsu, China Chinese regulatory requirements. All guardians of Participants were visited at home or came to the clinic [email protected] participants provided written informed consent. The at 5, 8, 11, and 14 months, when any medically signifi cant or study protocol is available online. events were recorded. Digital photographs were used to Zheng-Lun Liang, National identify participants throughout immunisation, blood Institute for Food and Drug Randomisation and masking collection, and site visits. Control, Tiantanxili, Beijing 100050, China Three consecutive batches of EV71 vaccine (numbers We did active surveillance of EV17-associated disease in [email protected] 201108002, 201108003, and 201108004) and one batch of all 485 clinics in villages, all 32 hospitals in townships, and or placebo (number 201108001) were used for this study in a the seven biggest public hospitals in cities, of all vaccinated Xin-Liang Shen, Beijing Vigoo 1:1:1:3 ratio. Each dose of vaccine and placebo was assigned participants from day 56 to month 14. Guardians were Biological, Sanjianfangnanli, a code from a randomisation list by block randomisation encouraged to take their children to treatment in clinics or ChaoYang District, Beijing (block size 30). The randomisation list was generated by hospitals for any illness during the surveillance period. 100024, China an external statistician with SAS (version 9.1). All pack- Unwell participants were screened for any of: HFMD-like [email protected] ages of vaccine and placebo were identical in appearance, illness, herpangina, acute respiratory symptoms or gastro- See Online for appendix with the code as the only identifi er. Each participant was intestinal symptoms, with or without other systemic For the protocol see http:// assigned a sequential number according to their sequence compli cations—eg, CNS complications and cardio pul- www.jscdc.cn/jkzt/jbkzzt/ of enrolment and received vaccine or placebo labelled with monary failure—but excluding those who had disease that szkb/jsgf_yg/201305/ the same numbers. Thus, participants were randomly was confi rmed not to involve EV71. All potential cases were t20130517_35229.html assigned to receive EV71 vaccine or placebo in a 1:1 ratio. reported by the clinics or hospitals. Throat or rectal swabs Investigators involved in randomisation and masking did or both were taken for pathogen detection within 24 h. The not participate in any other part of the trial. Allocation ad hoc local laboratories in each study centre—operated by was masked from all participants, their guardians, Jiangsu Mole Bioscience— tested for Coxsackie A virus 16, and investigators. EV71, and other enteroviruses by real-time PCR (fl uores- cence assay) with a viral RNA diagnostic kit. Participants Procedures who were positive for EV71-specifi c RNA were deemed Inactivated alum-adjuvanted EV71 vaccine (vero cell), suspected cases and were visited by study staff s to assess containing 320 U of antigen and 0·18 mg of alum, was exposure history and take acute blood samples, serial developed and manufactured by Beijing Vigoo Biological swabs, and stool samples. These samples were then with a seed virus of EV71 strain FY7VP5/AH/CHN/2008 shipped to the Chinese National Institute for Food and (genotype C4, which is the predominant strain in Drug Control to test for IgM antibody, EV71-specifi c RNA, mainland China).5 Each dose of placebo contains 0·18 mg virus isolation,13 and VP1 amplifi cation.